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Author Report for: Gupta RC

Title: Carbofuran pesticide toxicity to the eye
Kempuraj D, Zhang E, Gupta S, Gupta RC, Sinha NR, Mohan RR
Ref: Experimental Eye Research, :109355, 2022 : PubMed
Abstract


ESTHER: Kempuraj_2022_Exp.Eye.Res__109355
PubMedSearch: Kempuraj 2022 Exp.Eye.Res 109355
PubMedID: 36572166

Abstract

Pesticide exposure to eyes is a major source of ocular morbidities in adults and children all over the world. Carbofuran (CF), N-methyl carbamate, pesticide is most widely used as an insecticide, nematicide, and acaricide in agriculture, forestry, and gardening. Contact or ingestion of carbofuran causes high morbidity and mortality in humans and pets. Pesticides are absorbed in the eye faster than other organs of the body and damage ocular tissues very quickly. Carbofuran exposure to eye causes blurred vision, pain, loss of coordination, anti-cholinesterase activities, weakness, sweating, nausea and vomiting, abdominal pain, endocrine, reproductive, and cytotoxic effects in humans depending on amount and duration of exposure. Pesticide exposure to eye injures cornea, conjunctiva, lens, retina, and optic nerve and leads to abnormal ocular movement and vision impairment. Additionally, anticholinesterase pesticides like carbofuran are known to cause salivation, lacrimation, urination, and defecation (SLUD). Carbofuran and its two major metabolites (3-hydroxycarbofuran and 3-ketocarbofuran) are reversible inhibitors of acetylcholinesterase (AChE) which regulates acetylcholine (ACh), a neurohumoral chemical that plays an important role in corneal wound healing. The corneal epithelium contains high levels of ACh whose accumulation by AChE inhibition after CF exposure overstimulates muscarinic ACh receptors (mAChRs) and nicotinic ACh receptors (nAChRs). Hyper stimulation mAChRs in the eye causes miosis (excessive constriction of the pupil), dacryorrhea (excessive flow of tears), or chromodacryorrhea (red tears). Recent studies reported alteration of autophagy mechanism in human cornea in vitro and ex vivo post carbofuran exposure. This review describes carbofuran toxicity to the eye with special emphasis to corneal morbidities and blindness.



        

Title: Curcumin implants for continuous systemic delivery: safety and biocompatibility
Bansal SS, Kausar H, Aqil F, Jeyabalan J, Vadhanam MV, Gupta RC, Ravoori S
Ref: Drug Deliv Transl Res, 1:332, 2011 : PubMed
Abstract


ESTHER: Bansal_2011_Drug.Deliv.Transl.Res_1_332
PubMedSearch: Bansal 2011 Drug.Deliv.Transl.Res 1 332
PubMedID: 25788367

Abstract

Curcumin, an anti-oxidant, anti-inflammatory, and anti-neoplastic agent, exhibited limited oral efficacy due to its poor bioavailability. To overcome this limitation, polymeric implants for continuous systemic delivery of curcumin were developed and tested for their safety and biocompatibility. Two 2-cm polycaprolactone implants containing polyethylene glycol and 20% (w/w) curcumin were grafted subcutaneously at the back of the Augustus Copenhagen Irish rats. Rats were euthanized and blood was analyzed for various hematological parameters; biochemical markers of liver/kidney function and local tissues were analyzed for local inflammatory reactions. Curcumin implants exhibited biphasic release kinetics with -3.6 + 0.8, 5.8 +/- 1.1, 13.1 +/- 2.1, 21.8 +/- 0.3, 38.1 +/- 0.6, and 47.2 +/- 1.6 mg cumulative curcumin being released from both the implants after 1, 4, 12, 25, and 90 days. No significant differences in various hematological parameters (like white blood cells, red blood cells, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin), liver enzymes (like aspartate transaminase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, amylase, or lipase), or biochemical parameters of kidney function (like blood urea nitrogen, creatinine, Ca(2+), Na(+), and Cl(-) levels) were observed at any of these time points. However, a significant increase in serum phosphorus levels was observed at all the time points in sham implants as well as in curcumin diet and implant groups. Local implantation site showed foreign body granulomatous reaction with influx of histiocytes and occasional multi-nucleated giant cells with sham implants and was minimal around the curcumin implants. These polymeric implants were found to have little or no systemic toxicity with an acute reaction at local site which was reduced significantly by curcumin implants.



        

Title: Anatoxin-a(s): natural organophosphorus anticholinesterase agent
Patocka J, Gupta RC, Kuca K
Ref: Military Medical Science Letters, 80:129, 2011 : PubMed
Abstract


ESTHER: Patocka_2011_Mil.Med.Sci.Lett_80_129
PubMedSearch: Patocka 2011 Mil.Med.Sci.Lett 80 129
Inhibitor(s) related to this paper: Guanitoxin

Abstract

Anatoxin-a(s) is a guanidinemethyl phosphate ester isolated from the freshwater cyanobacterium (blue-green algae) Anabaena flos-aquae strain NRC 525-17. Previous work has shown anatoxin-a(s) to be a potent irreversible inhibitor of electric eel acetylcholinesterase (AChE, EC 3.1.1.7). Anatoxin-a(s) has been shown to be an active site-directed inhibitor of AChE, which is resistant to reactivation by oximes because of the enzyme-oxime adduct formation. In vivo pretreatment with physostigmine and high concentrations of pyridine 2-aldoxime methochloride (2-PAM) were the only effective antagonists against a lethal dose of anatoxin-a(s). Anatoxin-a(s) is very toxic and it is produced by cyanobacteria during its blooms. Purified toxin has an LD50 (i.p) of approximately 20-50 g/kg body weight in mice. Toxicoses associated with cholinesterase-inhibiting anatoxin-a(s) have been observed in humans, animals, birds and fish. Anatoxin-a(s) induces clinical signs of hypercholinergic preponderance, such as salivation, lacrimation, urinary incontinence, defecation, convulsion, fasciculation, and respiratory arrest.



        

Title: Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist
Zaja-Milatovic S, Gupta RC, Aschner M, Milatovic D
Ref: Toxicol Appl Pharmacol, 240:124, 2009 : PubMed
Abstract


ESTHER: Zaja-Milatovic_2009_Toxicol.Appl.Pharmacol_240_124
PubMedSearch: Zaja-Milatovic 2009 Toxicol.Appl.Pharmacol 240 124
PubMedID: 19615394

Abstract

Prophylactic agents acutely administered in response to anticholinesterases intoxication can prevent toxic symptoms, including fasciculations, seizures, convulsions and death. However, anticholinesterases also have long-term unknown pathophysiological effects, making rational prophylaxis/treatment problematic. Increasing evidence suggests that in addition to excessive cholinergic stimulation, organophosphate compounds such as diisopropylphosphorofluoridate (DFP) induce activation of glutamatergic neurons, generation of reactive oxygen (ROS) and nitrogen species (RNS), leading to neurodegeneration. The present study investigated multiple affectors of DFP exposure critical to cerebral oxidative damage and whether antioxidants and NMDA receptor antagonist memantine provide neuroprotection by preventing DFP-induced biochemical and morphometric changes in rat brain. Rats treated acutely with DFP (1.25 mg/kg, s.c.) developed onset of toxicity signs within 7-15 min that progressed to maximal severity of seizures and fasciculations within 60 min. At this time point, DFP caused significant (p<0.01) increases in biomarkers of ROS (F2-isoprostanes, F2-IsoPs; and F4-neuroprostanes, F4-NeuroPs), RNS (citrulline), and declines in high-energy phosphates (HEP) in rat cerebrum. At the same time, quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant (p<0.01) reductions in dendritic lengths and spine density. When rats were pretreated with the antioxidants N-tert-butyl-alpha-phenylnitrone (PBN, 200 mg/kg, i.p.), or vitamin E (100 mg/kg, i.p./day for 3 days), or memantine (18 mg/kg, i.p.), significant attenuations in DFP-induced increases in F2-IsoPs, F4-NeuroPs, citrulline, and depletion of HEP were noted. Furthermore, attenuation in oxidative damage following antioxidants or memantine pretreatment was accompanied by rescue from dendritic degeneration of pyramidal neurons in the CA1 hippocampal area. These findings closely associated DFP-induced lipid peroxidation with dendritic degeneration of pyramidal neurons in the CA1 hippocampal area and point to possible interventions to limit oxidative injury and dendritic degeneration induced by anticholinesterase neurotoxicity.



        

Title: Neuronal oxidative injury and dendritic damage induced by carbofuran: protection by memantine
Gupta RC, Milatovic S, Dettbarn WD, Aschner M, Milatovic D
Ref: Toxicol Appl Pharmacol, 219:97, 2007 : PubMed
Abstract


ESTHER: Gupta_2007_Toxicol.Appl.Pharmacol_219_97
PubMedSearch: Gupta 2007 Toxicol.Appl.Pharmacol 219 97
PubMedID: 17188316

Abstract

Carbamate insecticides mediate their neurotoxicity by acetylcholinesterase (AChE) inactivation. Male Sprague-Dawley rats acutely intoxicated with the carbamate insecticide carbofuran (1.5 mg/kg, sc) developed hypercholinergic signs within 5-7 min of exposure, with maximal severity characterized by seizures within 30-60 min, lasting for about 2 h. At the time of peak severity, compared with controls, AChE was maximally inhibited (by 82-90%), radical oxygen species (ROS) markers (F(2)-isoprostanes, F(2)-IsoPs; and F(4)-neuroprostanes, F(4)-NeuroPs) were elevated 2- to 3-fold, and the radical nitrogen species (RNS) marker citrulline was elevated 4- to 8-fold in discrete brain regions (cortex, amygdala, and hippocampus). In addition, levels of high-energy phosphates (HEPs) were significantly reduced (ATP, by 43-56%; and phosphocreatine, by 37-48%). Values of total adenine nucleotides and total creatine compounds declined markedly (by 41-56% and 35-45%, respectively), while energy charge potential remained unchanged. Quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant decreases in dendritic lengths (by 64%) and spine density (by 60%). Pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (18 mg/kg, sc), in combination with atropine sulfate (16 mg/kg, sc), significantly attenuated carbofuran-induced changes in AChE activity and levels of F(2)-IsoPs and F(4)-NeuroPs, declines in HEPs, as well as the alterations in morphology of hippocampal neurons. MEM and ATS pretreatment also protected rats from carbofuran-induced hypercholinergic behavioral activity, including seizures. These findings support the involvement of ROS and RNS in seizure-induced neuronal injury and suggest that memantine by preventing carbofuran-induced neuronal hyperactivity blocks pathways associated with oxidative damage in neurons.



        

Title: Modulation of parathion toxicity by glucose feeding: Is nitric oxide involved?
Liu J, Gupta RC, Goad JT, Karanth S, Pope C
Ref: Toxicol Appl Pharmacol, 219:106, 2007 : PubMed
Abstract


ESTHER: Liu_2007_Toxicol.Appl.Pharmacol_219_106
PubMedSearch: Liu 2007 Toxicol.Appl.Pharmacol 219 106
PubMedID: 17178140

Abstract

Glucose feeding can markedly exacerbate the toxicity of the anticholinesterase insecticide, parathion. We determined the effects of parathion on brain nitric oxide and its possible role in potentiation of toxicity by glucose feeding. Adult rats were given water or 15% glucose in water for 3 days and challenged with vehicle or parathion (18 mg/kg, s.c.) on day 4. Functional signs, plasma glucose and brain cholinesterase, citrulline (an indicator of nitric oxide production) and high-energy phosphates (HEPs) were measured 1-3 days after parathion. Glucose feeding exacerbated cholinergic toxicity. Parathion increased plasma glucose (15-33%) and decreased cortical cholinesterase activity (81-90%), with no significant differences between water and glucose treatment groups. In contrast, parathion increased brain regional citrulline (40-47%) and decreased HEPs (18-40%) in rats drinking water, with significantly greater changes in glucose-fed rats (248-363% increase and 31-61% decrease, respectively). We then studied the effects of inhibiting neuronal nitric oxide synthase (nNOS) by 7-nitroindazole (7NI, 30 mg/kg, i.p. x4) on parathion toxicity and its modulation by glucose feeding. Co-exposure to parathion and 7NI led to a marked increase in cholinergic signs of toxicity and lethality, regardless of glucose intake. Thus, glucose feeding enhanced the accumulation of brain nitric oxide following parathion exposure, but inhibition of nitric oxide synthesis was ineffective at counteracting increased parathion toxicity associated with glucose feeding. Evidence is therefore presented to suggest that nitric oxide may play both toxic and protective roles in cholinergic toxicity, and its precise contribution to modulation by glucose feeding requires further investigation.



        

Title: Anticholinesterase toxicity and oxidative stress
Milatovic D, Gupta RC, Aschner M
Ref: ScientificWorldJournal, 6:295, 2006 : PubMed
Abstract


ESTHER: Milatovic_2006_ScientificWorldJournal_6_295
PubMedSearch: Milatovic 2006 ScientificWorldJournal 6 295
PubMedID: 16518518

Abstract

Anticholinesterase compounds, organophosphates (OPs) and carbamates (CMs) are commonly used for a variety of purposes in agriculture and in human and veterinary medicine. They exert their toxicity in mammalian system primarily by virtue of acetylcholinesterase (AChE) inhibition at the synapses and neuromuscular junctions, leading into the signs of hypercholinergic preponderance. However, the mechanism(s) involved in brain/muscle damage appear to be linked with alteration in antioxidant and the scavenging system leading to free radical-mediated injury. OPs and CMs cause excessive formation of F2-isoprostanes and F4-neuroprostanes, in vivo biomarkers of lipid peroxidation and generation of reactive oxygen species (ROS), and of citrulline, a marker of NO/NOS and reactive nitrogen species (RNS) generation. In addition, during the course of these excitatory processes and inhibition of AChE, a high rate of ATP consumption, coupled with the inhibition of oxidative phosphorylation, compromise the cell's ability to maintain its energy levels and excessive amounts of ROS and RNS may be generated. Pretreatment with N-methyl D-aspartate (NMDA) receptor antagonist memantine, in combination with atropine sulfate, provides significant protection against inhibition of AChE, increases of ROS/RNS, and depletion of high-energy phosphates induced by DFP/carbofuran. Similar antioxidative effects are observed with a spin trapping agent, phenyl-N-tert-butylnitrone (PBN) or chain breaking antioxidant vitamin E. This review describes the mechanisms involved in anticholinesterase-induced oxidative/nitrosative injury in target organs of OPs/CMs, and protection by various agents.



        

Title: Carbofuran-induced oxidative stress in slow and fast skeletal muscles: prevention by memantine and atropine
Milatovic D, Gupta RC, Dekundy A, Montine TJ, Dettbarn WD
Ref: Toxicology, 208:13, 2005 : PubMed
Abstract


ESTHER: Milatovic_2005_Toxicology_208_13
PubMedSearch: Milatovic 2005 Toxicology 208 13
PubMedID: 15664429

Abstract

Acute toxic effects of acetylcholinesterase (AChE) inhibitors on skeletal muscles are thought to involve oxidative stress with increased generation of free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). Muscle hyperactivity with its increased oxygen and energy consumption appear to be the primary cause of oxidative stress. The present investigation was therefore undertaken to establish the normal levels of F(2)-isoprostanes (F(2)-IsoPs, specific markers of ROS/oxidative stress), citrulline (determinant of NO/NOS and marker of RNS), and high-energy phosphates (HEP: adenosine triphosphate, ATP and phosphocreatine, PCr) in slow (soleus) and fast (extensor digitorum longus, EDL) muscles of rats. In addition, we aimed to determine if memantine HCl (MEM), in combination with atropine sulfate (ATS), prevents carbofuran-induced changes in markers of oxidative stress. Control values were not significantly different for F(2)-IsoPs (1.142 +/- 0.027 and 1.177 +/- 0.092 ng/g) and citrulline (469.7 +/- 31.8 and 417.8 +/- 18.5 nmol/g) in soleus and EDL muscles, while the values were different for HEP (ATP, 3.66 +/- 0.11 and 5.85 +/- 0.14 micromol/g; PCr, 7.91 +/- 0.26 and 13.14 +/- 0.31 micromol/g). Rats acutely intoxicated with carbofuran (1.5 mg/kg, s.c.) showed the signs of maximal toxicity including muscle hyperactivity within 60 min of exposure. At this time, F(2)-IsoPs (177 and 153%) and citrulline (267 and 304%) levels were significantly increased, while ATP (46 and 43%) and PCr (44 and 46%) levels were decreased in soleus and EDL, respectively. Rats pretreated with MEM (18 mg/kg, s.c.) and ATS (16 mg/kg, s.c.), 60 and 15 min prior to carbofuran, respectively, showed no signs of toxicity. MEM in combination with ATS protected muscles from carbofuran-induced hyperactivity and attenuated increases in F(2)-IsoPs and citrulline, and depletion of HEP. Carbofuran-induced changes and protection by MEM and ATS were of similar magnitude in both muscles. These findings indicate that carbofuran-induced muscle hyperactivity produces oxidative stress as measured by increased ROS and RNS generation, and HEP depletion. MEM and ATS prevent the carbofuran-induced chain of events involved in oxidative stress.



        

Title: Involvement of nitric oxide in myotoxicity produced by diisopropylphosphorofluoridate (DFP)-induced muscle hyperactivity
Gupta RC, Milatovic D, Dettbarn WD
Ref: Archives of Toxicology, 76:715, 2002 : PubMed
Abstract


ESTHER: Gupta_2002_Arch.Toxicol_76_715
PubMedSearch: Gupta 2002 Arch.Toxicol 76 715
PubMedID: 12451448

Abstract

Oxidative stress, as determined by increased lipid peroxidation, has been implicated in the pathology of myotoxicity. As a model system to study the response of muscle to oxidative insults, we have studied the effects of diisopropylphosphorofluoridate (DFP)-induced muscle hyperactivity on levels of nitric oxide (NO) and energy metabolites in rat skeletal muscles. In in vivo experiments, citrulline levels as indicators of NO and NO synthase (NOS), and ATP and phosphocreatine (PCr) as indicators of mitochondrial dysfunction, were determined using HPLC methods 15 min, 30 min, 60 min, 2 h, and 24 h after intoxication. Within 15 min of DFP exposure, with onset of fasciculations, citrulline levels were significantly elevated in all three muscles [soleus, extensor digitorum longus (EDL), and diaphragm]. Maximum increases in citrulline (272-288%) were noted 60 min after DFP injection. At this time point, acetylcholinesterase activity was reduced by 90-96% (soleus < diaphragm < EDL). The levels of ATP and PCr were maximally reduced (30-43%), and total adenine nucleotides, and total creatine compounds showed declines. The findings revealed that the increase in NOS activity and NO was greater than the decrease of ATP and PCr. Since memantine (MEM) has been shown to reduce nerve and muscle hyperactivity, we have studied the possible protective effect of MEM on the DFP-induced biochemical changes. Pretreatment with MEM (18 mg/kg s.c.) and atropine sulfate (16 mg/kg s.c.), 60 min and 15 min, respectively, before DFP injection prevented the increase in citrulline and muscle hyperactivity and the decrease in ATP and PCr. These data suggest that free radical reactions by depleting high-energy phosphates may be initiating the cascade of events leading to myotoxicity during DFP-induced muscle hyperactivity.



        

Title: Nitric oxide modulates high-energy phosphates in brain regions of rats intoxicated with diisopropylphosphorofluoridate or carbofuran: prevention by N-tert-butyl-alpha-phenylnitrone or vitamin E
Gupta RC, Milatovic D, Dettbarn WD
Ref: Archives of Toxicology, 75:346, 2001 : PubMed
Abstract


ESTHER: Gupta_2001_Arch.Toxicol_75_346
PubMedSearch: Gupta 2001 Arch.Toxicol 75 346
PubMedID: 11570692

Abstract

Acute effects of seizure-inducing doses of the organophosphate compound diisopropylphosphorofluoridate (DFP, 1.25 mg/kg s.c.) or the carbamate insecticide carbofuran (CF, 1.25 mg/kg s.c.) on nitric oxide (NO) were studied in the brain of rats. Brain regions (pyriform cortex, amygdala, and hippocampus) were assayed for citrulline as the determinant of NO and for high-energy phosphates (ATP and phosphocreatine) as well as their major metabolites (ADP, AMP, and creatine). Rats, anesthetized with sodium pentobarbital (50 mg/kg i.p.), were killed using a head-focused microwave (power, 10 kW; duration, 1.7 s). Analyses of brain regions of controls revealed significantly higher levels of citrulline in the amygdala (289.8+/-7.0 nmol/g), followed by the hippocampus (253.8+/-5.5 nmol/g), and cortex (121.7+/-4.3 nmol/g). Levels of energy metabolites were significantly higher in cortex than in amygdala or hippocampus. Within 5 min of CF injection, the citrulline levels were markedly elevated in all three brain regions examined, while with DFP treatment, only the cortex levels were elevated at this time. With either acetylcholinesterase (AChE) inhibitor, the maximum increase in citrulline levels was noted 30 min post-injection (> 6- to 7-fold in the cortex, and > 3- to 4-fold in the amygdala or hippocampus). Within 1 h following DFP or CF injection, marked declines in ATP (36-60%) and phosphocreatine (28-53%) were seen. Total adenine nucleotides and total creatine compounds were reduced (36 58% and 28-48%, respectively). The inverse relationship between the increase in NO and the decease in high-energy phosphates, could partly be due to NO-induced impaired mitochondrial respiration leading to depletion of energy metabolites. Pretreatment of rats with an antioxidant, the spin trapping agent N-tert-butyl-alpha-phenylnitrone (PBN, 200 mg/kg i.p.), prevented DFP- or CF-induced seizures, while the antioxidant vitamin E (100 mg/kg i.p. per day for 3 days) had no anticonvulsant effect. Both antioxidants, however, significantly prevented the increase of citrulline and the depletion of high-energy phosphates. It is concluded that seizures induced by DFP and CF produce oxidative stress due to a marked increase in NO, causing mitochondrial dysfunction, and thereby depleting neuronal energy metabolites. PBN pretreatment provides protection against AChE inhibitor-induced oxidative stress mainly by preventing seizures. Additional antioxidant actions of PBN may contribute to its protective effects. Vitamin E has direct antioxidant effects by preventing excessive NO production.



        

Title: Depletion of energy metabolites following acetylcholinesterase inhibitor-induced status epilepticus: protection by antioxidants
Gupta RC, Milatovic D, Dettbarn WD
Ref: Neurotoxicology, 22:271, 2001 : PubMed
Abstract


ESTHER: Gupta_2001_Neurotoxicol_22_271
PubMedSearch: Gupta 2001 Neurotoxicol 22 271
PubMedID: 11405258

Abstract

Status epilepticus (SE)-induced neuronal injury may involve excitotoxicity, energy impairment and increased generation of reactive oxygen species (ROS). Potential treatment therefore should consider agents that protect mitochondrial function and ROS scavengers. In the present study, we examined whether the spin trapping agent N-tertbutyl-alpha-phenylnitrone (PBN) and the antioxidant vitamin E (DL-alpha-tocopherol) protect levels of high-energy phosphates during SE. In rats, SE was induced by either of two inhibitors of acetylcholinesterase (AChE), the organophosphate diisopropylphosphorofluoridate (DFP, 1.25 mg/kg, sc)- or the carbamate carbofuran (1.25 mg/kg, sc). Rats were sacrificed 1 h or 3 days after onset of seizures by head-focused microwave (power, 10 kW; duration 1.7 s) and levels of the energy-rich phosphates adenosine triphosphate (ATP) and phosphocreatine (PCr) and their metabolites adenosine diphosphate (ADP) and adenosine monophosphate (AMP), and creatine (Cr), respectively, were determined in the cortex, amygdala and hippocampus. Within 1 h of seizure activity, marked declines were seen in ATP (34-60%) and PCr (25-52%). Total adenine nucleotides (TAN = ATP + ADP + AMP) and total creatine compounds (TCC = PCr + Cr) were also reduced (TAN 38-60% and TCC 25-47%). No changes in ATP/AMP ratio were seen. Three days after the onset of seizures, recovery of ATP and PCr was significant in the amygdala and hippocampus, but not in the cortex. Pretreatment of rats with PBN (200 mg/kg, ip, in a single dose), 30 min before DFP or carbofuran administration, prevented induced seizures and partially prevented depletion of high-energy phosphates. Pretreatment with the natural antioxidant vitamin E (100 mg/kg, ip/day for 3 days), partially prevented loss of high energy phosphates without affecting seizures. In controls, citrulline, a product of nitric oxide synthesis, was found to be highest in the amygdala, followed by hippocampus, and lowest in the cortex. DFP- or carbofuran-induced seizures caused elevation of citrulline levels seven- to eight-fold in the cortex and three- to four-fold in the amygdala and hippocampus. These results suggest a close relationship between SE, excitotoxicity and energy metabolism. The involvement of oxidative stress is supported by the findings that DFP and carbofuran trigger an excessive nitric oxide (NO) production in the seizure relevant regions of the brain.



        

Title: Cholinergic and noncholinergic brain biomarkers of insecticide exposure and effects
Gupta RC, Goad JT, Milatovic D, Dettbarn WD
Ref: Hum Exp Toxicol, 19:297, 2000 : PubMed
Abstract


ESTHER: Gupta_2000_Hum.Exp.Toxicol_19_297
PubMedSearch: Gupta 2000 Hum.Exp.Toxicol 19 297
PubMedID: 10918524

Abstract

The objective of this investigation was to determine the distribution of cholinergic and noncholinergic biomarkers in discrete brain regions (cortex, stem, striatum, hippocampus, and cerebellum) of rats treated with dimethyl sulfoxide (DMSO, controls), and insecticides such as carbofuran (CARB, 1.5 mg/kg, sc), or methyl parathion (MPTH, 5 mg/kg, ip). Both insecticides produced characteristic signs of anticholinesterase nature within 5-7 min after injection. In controls, analyses of the brain regions revealed a wide variability in the values of cholinergic (acetylcholinesterase, AChE) and noncholinergic (creatine kinase, CK; and lactic dehydrogenase, LDH, and their isoenzymes) biomarkers. The highest activities of AChE and LDH were found in the striatum (1661+/-23 micromol/g/h and 57,720+/-478 IU/l, respectively) and lowest in the cerebellum (118+/-6 micromol/g/h) and 39,480+/-918 IU/l, respectively). However, the activity of CK was found highest in the cerebellum (742,560+/-798 IU/l) and lowest in the hippocampus (353,400+/-11,696 IU/l). Each brain region showed a characteristic profile of CK and LDH isoenzymes. Among the CK isoenzymes, activity of CK-BB was highest (77.5-89.3%), followed by CK-MM (6.7-15.6%), and least CK-MB (0-6.9%). The cerebellum had no CK-MB activity. In all brain regions, CK-MM isoenzyme had only the CK-MM3 subform. Among the LDH isoenzymes, activity of LDH-4 was highest in all brain regions (23-40%), except the cerebellum in which LDH-1 was highest (29%). Compared to the brain, control serum contained very little CK and LDH activity, but serum had three distinct CK and five distinct LDH isoenzymes. Unlike brain regions, serum had three CK-MM subforms. Each insecticide induced characteristic alterations in brain biomarkers. AChE activity was maximally inactivated in cortex (90. 6%) with CARB, and in cerebellum (95.3%) with MPTH. With either insecticide, the least inhibition of AChE occurred in the striatum. Unlike AChE, carboxylesterase (CarbE) did not show brain regional variability in controls, and its activity was uniformly inhibited in all brain regions by CARB and comparatively greater by MPTH. CARB- or MPTH-induced characteristic alterations in CK, LDH, and their isoenzymes in the brain, which were also reflected in serum, as a result of their leakage from the brain by increased permeability due to depletion of ATP (38-57% and 33-47%, respectively) and phosphocreatine (PCr, 23-42% and 56-65%, respectively).



        

Title: Energy related metabolic alterations in diaphragm muscle resulting from acute methomyl toxicity
Gupta RC, Goad JT, Kadel WL
Ref: Neurotoxicology, 15:321, 1994 : PubMed
Abstract


ESTHER: Gupta_1994_Neurotoxicol_15_321
PubMedSearch: Gupta 1994 Neurotoxicol 15 321
PubMedID: 7991221
Inhibitor(s) related to this paper: Methomyl

Abstract

Male Sprague-Dawley rats receiving an acute dose of methomyl (5 mg/Kg, sc) developed overt signs of toxicity within 2 min. The maximum severity, including muscle fasciculations and convulsions, was attained within 7-10 min and lasted for about 30 min. A very rapid recovery followed and by 90 min rats were free from obvious toxicity. During intoxication, the body temperature was significantly below normal. In diaphragm, when the activity of acetylcholinesterase (AChE) was markedly depressed (82%), the levels of high-energy phosphates, adenosine triphosphate (ATP) and phosphocreatine (PCr) were also significantly lowered (27% and 54%, respectively). Significant decreases in the levels of adenosine diphosphate (ADP, 19%), total adenine nucleotides (TAN, 27%), creatine (Cr, 27%), and total creatine compounds (TCrC, 29%) were noted at various intervals. The ratio of PCr/Cr was reduced by 53%. The adenylate energy charge [(ATP + 1/2 ADP)/(ATP + ADP + AMP)], an indicator of high-energy phosphate bond availability, remained unchanged throughout the time course. More than twofold elevation in the activity of Mg(2+)-facilitated creatine kinase (reverse Lohmann reaction) in diaphragm (CK-MM) and more than twofold increase in the levels of glucose in serum, were suggestive of greater synthesis of ATP. Higher activity of CK-MM was also noted in the serum. That high-energy phosphates were partially depleted suggested that the rate of ATP utilization was far greater than its synthesis. Methomyl intoxication also resulted in higher activity of LDH and its isoenzymes in muscle as a result of induced greater synthesis. Elevation of CK and LDH and their isoenzymes in the serum was probably a result of their leakage from the tissues due to loss of membrane permeability caused by significant depletion of ATP and PCr.



        

Title: Cholinergic and noncholinergic changes in skeletal muscles by carbofuran and methyl parathion
Gupta RC, Goad JT, Kadel WL
Ref: Journal of Toxicology & Environmental Health, 43:291, 1994 : PubMed
Abstract


ESTHER: Gupta_1994_J.Toxicol.Env.Health_43_291
PubMedSearch: Gupta 1994 J.Toxicol.Env.Health 43 291
PubMedID: 7966439

Abstract

The objective of this investigation was to determine the distribution of cholinergic (acetyl-cholinesterase, AChE) and noncholinergic markers in slow-, fast-, and mixed-fiber containing muscles (soleus, SOL; extensor digitorum longus, EDL; and diaphragm, DIA, respectively). Noncholinergic markers included high-energy phosphates (adenosine triphosphate, ATP; phosphocreatine, PCr; and their metabolites), and the activity of creatine kinase (CK) and lactate dehydrogenase (LDH) and their isoenzymes and subforms. All three types of muscles had only one CK isoenzyme, CK-MM, which totally consisted of MM3 subform. Levels of these determinants were highest in EDL followed by DIA and least in SOL. Another objective was to determine alterations of these markers under the influence of acute carbofuran (1.5 mg/kg) or methyl parathion (MPTH, 5 mg/kg) toxicity. Rats receiving either insecticide showed cholinergic signs with maximal severity including muscle fasciculations and convulsions within 15-30 min that lasted for about 2 h. At 1 h postinsecticide injection, when AChE was maximally inhibited (81-96%), significant depletion of ATP and PCr was evident in muscles (DIA > SOL > EDL), and activities of CK-MM and LDH were elevated in muscles and consequently in serum. Serum CK-MM3 activity was markedly reduced with sequential increase in MM2 and MM1 subforms, probably due to induced higher carboxypeptidase activity. These findings suggested that (1) the differences in levels of biochemical constituents in muscles depend upon the fiber type, (2) anticholinesterase insecticide-induced increased muscle activity produces characteristic changes in CK and LDH isoenzymes patterns, and (3) leakage of these enzymes/isoenzymes into serum is due to depletion of ATP and PCr, which are required to maintain the cell membrane permeability.



        

Title: Role of carboxylesterases in the prevention and potentiation of N-methylcarbamate toxicity
Gupta RC, Dettbarn WD
Ref: Chemico-Biological Interactions, 87:295, 1993 : PubMed
Abstract


ESTHER: Gupta_1993_Chem.Biol.Interact_87_295
PubMedSearch: Gupta 1993 Chem.Biol.Interact 87 295
PubMedID: 8343987

Abstract

Pretreatment of rats with iso-OMPA one hour prior to each of the N-methylcarbamate insecticides, carbofuran, propoxur, or aldicarb, potentiated the toxicity of these carbamates threefold. None of these compounds alone in the dosage used produced toxic signs; however, carboxylesterase (CarbE) activity in a variety of organs including brain, muscle, liver, and plasma was significantly reduced, while acetylcholinesterase (AChE) activity was unchanged. Significant inhibition of AChE was observed after the combination of tetraisopropylpyrophosphoramide (iso-OMPA) with each one of these N-methylcarbamates. It is suggested that CarbEs are more sensitive than AChE to these N-methylcarbamates and inhibition of CarbE by iso-OMPA raises the concentration of N-methylcarbamates available to inhibit AChE resulting in increased toxicity. Other N-methylcarbamates such as physostigmine do not inhibit CarbE, nor are their toxicities potentiated by iso-OMPA.



        

Title: Potential of memantine, D-tubocurarine, and atropine in preventing acute toxic myopathy induced by organophosphate nerve agents: soman, sarin, tabun and VX
Gupta RC, Dettbarn WD
Ref: Neurotoxicology, 13:649, 1992 : PubMed
Abstract


ESTHER: Gupta_1992_Neurotoxicol_13_649
PubMedSearch: Gupta 1992 Neurotoxicol 13 649
PubMedID: 1475066
Inhibitor(s) related to this paper: Sarin, Soman, Tabun, VX

Abstract

Male Sprague-Dawley rats when administered sc a sublethal dose of organophosphorus cholinesterase inhibitors such as the nerve agents, soman (100 micrograms/kg, sc), sarin (110 micrograms/kg, sc), tabun (200 micrograms/kg, sc), or VX (12 micrograms/kg, sc), developed seizures and severe muscle fasciculations within 15-20 min, lasting for 4-6 hr. Marked inhibition of acetylcholinesterase (AChE) and necrotic lesions in skeletal muscles such as soleus, extensor digitorum longus, and diaphragm were evident between 1-24 hr following injection. Pretreatment with memantine HCl (MEM, 18 mg/kg, sc) together with atropine sulfate (ATS, 16 mg/kg, sc), 60 min and 15 min, respectively, prior to nerve agents attenuated AChE inhibition, prevented myonecrosis, and muscle fasciculations as well as other signs of cholinergic toxicity. Pretreatment combining d-tubocurarine (d-TC, 0.075 mg/kg, sc) and ATS (16 mg/kg, sc) prevented the myonecrosis and fasciculation without protecting AChE against inhibition by these nerve agents. Neither MEM, d-TC, nor ATS in the concentration given interfered with the normal behavior of the rats. The role of d-TC and ATS interaction with presynaptic receptors regulating ACh release and MEM's role in modulating neural hyperactivity as protective mechanisms are discussed.



        

Title: In Vivo Regulation of Acetylcholinesterase in Slow and Fast Muscle of Rat
Dettbarn WD, Groswald DE, Gupta RC, Misulis KE, Patterson GT
Ref: In: Cholinesterases: Structure, Function, Mechanism, Genetics, and Cell Biology, (Massoulie J, Barnard EA, Chatonnet A, Bacou F, Doctor BP, Quinn DM) American Chemical Society, Washington, DC:71, 1991 : PubMed
Abstract


ESTHER: Dettbarn_1991_3rd.ChE.Meeting.LaGrandeMotte__71
PubMedSearch: Dettbarn 1991 3rd.ChE.Meeting.LaGrandeMotte 71



        

Title: Comparison of cholinergic and neuromuscular toxicity following acute exposure to sarin and VX in rat
Gupta RC, Patterson GT, Dettbarn WD
Ref: Fundamental & Applied Toxicology, 16:449, 1991 : PubMed
Abstract


ESTHER: Gupta_1991_Fundam.Appl.Toxicol_16_449
PubMedSearch: Gupta 1991 Fundam.Appl.Toxicol 16 449
PubMedID: 1855618
Inhibitor(s) related to this paper: Sarin, VX

Abstract

Male Sprague-Dawley rats injected with a sublethal sc dosage of 110 micrograms/kg of sarin (isopropyl methylphosphonofluoridate), or 12 micrograms/kg of VX (S-(2-diisopropylaminoethyl) O-ethyl methylphosphonothioate), developed severe toxic signs within 5-15 min after sarin and 20-50 min after VX lasting for 5 to 7 hr. Myonecrotic lesions were seen in soleus and diaphragm muscles within 1 hr. A maximum number of lesions had developed after 24 hr, and lesions were also present in extensor digitorum longus (EDL) at this time. Regeneration of muscle fibers was slow since lesions were still evident past 7 days of treatment. Within 1 hr following VX, AChE activity was reduced to 8, 12, and 17% of control activity in soleus, diaphragm, and EDL, respectively, whereas with sarin the enzyme activity was reduced to 23, 48, and 82% of control. A still greater inhibition was seen 24 hr after sarin when AChE activity was reduced to 19, 13, and 43% in these muscles. In skeletal muscles the different molecular forms of AChE, such as 16 S, 12 S, 10 S, and 4 S vary in location and functional importance with the 16 S form highly concentrated at the neuromuscular junction. All forms in a given muscle were equally sensitive to the inhibitors. In EDL, sarin was the least effective in reducing AChE or its molecular forms. In the brain structures (cortex, brain stem, striatum, and hippocampus), AChE activity was reduced to 1-6% of control by sarin and VX with the exception that following VX striatal AChE was reduced to only 41% of control activity. AChE activity in the brain cortex following either of the agents was maximally affected (1%). A slow but significant recovery of brain AChE was evident after 24 hr and more so after Day 7. Butyrylcholinesterase (BCHE) activity was less sensitive to inhibition by both inhibitors compared to AChE activity and showed a rapid recovery. Based on the equitoxic doses (toxic signs of similar magnitude), VX was found to be 10 times more toxic than sarin. The mechanisms of this disparity may be due to differences in rate of uptake, circulation, susceptibility to hydrolysis, and reactivity with nonspecific binding sites.



        

Title: Concerted role of carboxylesterases in the potentiation of carbofuran toxicity by iso-OMPA pretreatment
Gupta RC, Kadel WL
Ref: J Toxicol Environ Health, 26:447, 1989 : PubMed
Abstract


ESTHER: Gupta_1989_J.Toxicol.Environ.Health_26_447
PubMedSearch: Gupta 1989 J.Toxicol.Environ.Health 26 447
PubMedID: 2709439

Abstract

Pretreatment of rats with the nonspecific esterase inhibitor iso-OMPA (1 mg/kg sc) 1 h prior to carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-methylcarbamate, 0.5 mg/kg sc) administration potentiated carbofuran toxicity by more than threefold. Neither iso-OMPA nor carbofuran in the given doses produced any gross toxic signs. Rats receiving combined treatment, however, showed severe hypercholinergic signs (salivation, tremors, muscle fasciculations, and convulsions) within 5-10 min following carbofuran administration, and the severity was comparatively greater than that observed with an acute dose of carbofuran (1.5 mg/kg sc). Rats pretreated with iso-OMPA (0.5 mg/kg) died within 10-15 min following the acute dose of carbofuran (1.5 mg/kg). Each drug when given alone (1.0 mg/kg iso-OMPA, 0.5 mg/kg carbofuran) caused a significant (p less than .01) inhibition of carboxylesterase (CarbE) activity in brain structures (cortex, stem, striatum, and hippocampus), skeletal muscle (hemidiaphragm), liver, and plasma, whereas acetylcholinesterase (AChE) activity remained significantly (p greater than .01) unchanged. The maximal CarbE inactivation in plasma (less than 14% remaining activity) following either drug indicated a tremendous nonspecific binding to non-AChE serine-containing enzymes. iso-OMPA pretreatment markedly potentiated carbofuran's anticholinesterase activity both in neuronal and in nonneuronal tissues. It can be concluded that iso-OMPA pretreatment potentiates carbofuran toxicity either by preventing nonspecific binding of carbofuran to CarbE and/or possibly by inhibiting its detoxification.



        

Title: Biochemical and histochemical alterations following acute soman intoxication in the rat
Gupta RC, Patterson GT, Dettbarn WD
Ref: Toxicol Appl Pharmacol, 87:393, 1987 : PubMed
Abstract


ESTHER: Gupta_1987_Toxicol.Appl.Pharmacol_87_393
PubMedSearch: Gupta 1987 Toxicol.Appl.Pharmacol 87 393
PubMedID: 3564014

Abstract

Rats injected with a nonlethal acute dose (100 micrograms/kg, sc) of soman (pinacolyl methylphosphonofluoridate) exhibited signs of anticholinesterase toxicity beginning at 5-15 min with increasing severity and lasting for 4-6 hr. Generalized tremors and seizure activity indicated comparatively greater involvement of the central cholinergic system than peripheral neuromuscular effects. During peak toxicity, all the brain regions tested showed more than 95% inhibition of acetylcholinesterase (AChE) activity. The cortex area was maximally affected (99% inhibition). Among skeletal muscles, soleus AChE was most severely affected (94%) and extensor digitorum longus (EDL) the least (72%). Inhibition of EDL AChE occurred at a much slower rate than in brain and other muscles. Significant recovery of AChE activity was seen by 48-72 hr after soman treatment in both brain and skeletal muscles. By Day 7, recovery was virtually complete in skeletal muscles but not in brain, although significant recovery had occurred by this time. Muscle fiber necrosis developed within 6 hr in the soleus and diaphragm, while no necrotic fibers were found in the EDL. The 16 S AChE molecular form showed the fastest recovery of the AChE isozymes in all three muscles. Full recovery was seen after 7 days in soleus and was increased to greater than control activity in diaphragm and EDL. The inhibition pattern of butyrylcholinesterase (BCHE) activity was similar to that described for AChE activity, but the recovery was comparatively faster. Carboxylesterase activity in plasma was decreased to less than 10% of control within 1 hr and recovered to 53% of control within 24 hr. No significant inhibition was seen in hepatic carboxylesterase activity. It can be concluded that soman-induced acute toxicity is directly related to the rate and degree of AChE inhibition. A significant amount of soman binds to non-AChE enzymes with serine sites such as BCHE and carboxylesterases.



        

Title: Interaction of cycloheximide and diisopropylphosphorofluoridate (DFP) during subchronic administration in rat
Gupta RC, Dettbarn WD
Ref: Toxicol Appl Pharmacol, 90:52, 1987 : PubMed
Abstract


ESTHER: Gupta_1987_Toxicol.Appl.Pharmacol_90_52
PubMedSearch: Gupta 1987 Toxicol.Appl.Pharmacol 90 52
PubMedID: 3629591

Abstract

Male Sprague-Dawley rats daily treated with DFP (0.5 mg/kg/day, sc) exhibited signs of cholinergic toxicity such as tremors and muscle fasciculations between Days 3 and 5 comparable to those observed 15 min after a single acute signs-producing dose (1.5 mg/kg, sc). Further administration of DFP (0.5 mg/kg/day, sc) for 6-14 days led to tolerance development as evidenced by disappearance of the described toxicity signs. The protein synthesis inhibitor cycloheximide, when given in a nontoxic dose (0.5 mg/kg/day, sc) 1 hr before DFP (0.5 mg/kg/day, sc) administration, potentiated the DFP toxicity and rats died after the fifth injection. DFP-tolerant rats developed toxicity signs when subsequently treated with cycloheximide (0.5 mg/kg/day, sc) and DFP (0.5 mg/kg/day, sc). Each drug when given alone for 4 days caused 30-50% reduction of [14C]valine uptake in vivo into the free amino acids pool as well as its incorporation into proteins of brain and skeletal muscles. A combination of these drugs caused a significantly greater inhibitory effect on [14C]valine incorporation into proteins. Cycloheximide (0.5 mg/kg/day, sc) administered for 4 days did not significantly alter the levels of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), or carboxylesterase (CarbE) activities but potentiated the DFP-induced inhibition of the activities of these enzymes. It is concluded that the cycloheximide pretreatment potentiates DFP toxicity by a mechanism that is related to inhibition of the synthesis of proteins such as AChE, BuChE, and CarbE.



        

Title: Acute tabun toxicity; biochemical and histochemical consequences in brain and skeletal muscles of rat
Gupta RC, Patterson GT, Dettbarn WD
Ref: Toxicology, 46:329, 1987 : PubMed
Abstract


ESTHER: Gupta_1987_Toxicology_46_329
PubMedSearch: Gupta 1987 Toxicology 46 329
PubMedID: 3672538
Inhibitor(s) related to this paper: Tabun

Abstract

Male Sprague-Dawley rats injected s.c. with an acute non-lethal dose (200 micrograms/kg) of ethyl N,N-dimethylphosphoramidocyanidate (tabun) showed onset of hypercholinergic activity within 10-15 min. The maximal severity of toxicity signs was evident within 0.5-1 h and persisted for 6 h. Except for mild tremors no overt toxicity signs were evident after 24 h. Within 1 h a dramatic decline of acetylcholinesterase (AChE) activity occurred in all the brain structures (less than 3%) and skeletal muscles (less than 10% in soleus and hemi-diaphragm; and 32% in extensor digitorum longus (EDL)). No significant recovery was seen up to 48-72 h. Within 7 days rats became free of toxicity signs and AChE activity had recovered to about 40% in brain structures (except cortex, 14%) and 65-70% in skeletal muscles. Within 1 h the 16 S molecular form of AChE located at the neuromuscular junction was most severely inhibited in soleus, followed by hemi-diaphragm and least in the EDL, and had fully recovered in all the muscles when examined after day 7. Muscle fiber necrosis developed within 1-3 h in soleus and hemi-diaphragm and after a delay of 24 h in EDL. The highest number of necrotic lesions in all muscles was seen at 72 h with the hemi-diaphragm maximally affected and EDL the least. To determine detoxification of tabun by non-specific binding, the activity of butyrylcholinesterase (BCHE) and carboxylesterase (CarbE) was measured. The inhibition and recovery pattern of BCHE activity was quite similar to that of AChE, except that the rate of recovery was more rapid. Within 1 h the remaining activity of CarbE was 10% in plasma, about 30% in brain structures, and 79% in liver; recovery was complete within 7 days. The inhibition of BCHE and CarbE can serve as a protective mechanism against tabun toxicity by reducing the amount available for AChE inhibition. The prolonged AChE inhibition in muscle and brain may indicate storage of tabun and delayed release from non-enzymic sites. Since tabun is a cyanophosphorus compound, the toxic effects from the released cyanide (CN) could be another reason for the delayed recovery after tabun.



        

Title: iso-OMPA-induced potentiation of soman toxicity in rat
Gupta RC, Dettbarn WD
Ref: Archives of Toxicology, 61:58, 1987 : PubMed
Abstract


ESTHER: Gupta_1987_Arch.Toxicol_61_58
PubMedSearch: Gupta 1987 Arch.Toxicol 61 58
PubMedID: 3439875

Abstract

Male Sprague-Dawley rats, injected with the irreversible acetylcholinesterase (AChE) inhibitor soman (pinacolyl methylphosphonofluoridate) 25 micrograms/kg sc, showed no signs of toxicity. Pretreatment with iso-OMPA (tetraisopropylpyrophosphoramide) 1 mg/kg sc 1 h before the soman administration, caused severe signs of hypercholinergic activity, similar to those seen with an acute signs-producing nonlethal dosage (100 micrograms soman/kg sc). Within 1 h iso-OMPA alone significantly reduced the activity of carboxylesterases (CarbE) in all tissues studied and butyrylcholinesterase (BCHE) activity was significantly reduced in plasma (22%) and liver (27%). Soman (25 micrograms/kg) alone significantly reduced the plasma activity of CarbE (15%), BCHE (53%) and AChE (18%), but had no effect on these enzymes of liver. The combined treatment of iso-OMPA and soman, however, reduced CarbE activity in liver (0%) and produced significantly greater effects than iso-OMPA or soman alone on AChE and BCHE in all the brain areas and skeletal muscles tested. The number of necrotic lesions found in skeletal muscles was many times higher with the combined treatment than seen with soman (25 micrograms/kg) alone, and was equal to those seen with an acute toxicity signs-producing dose of soman. It is concluded that the observed iso-OMPA-induced potentiation of soman toxicity is probably caused via reduced nonspecific binding sites (BCHE and CarbE) for soman leading to greater inhibition of AChE.



        

Title: Mechanisms involved in the development of tolerance to DFP toxicity
Gupta RC, Patterson GT, Dettbarn WD
Ref: Fundamental & Applied Toxicology, 5:S17, 1985 : PubMed
Abstract


ESTHER: Gupta_1985_Fundam.Appl.Toxicol_5_S17
PubMedSearch: Gupta 1985 Fundam.Appl.Toxicol 5 S17
PubMedID: 4092885
Inhibitor(s) related to this paper: DFP, Iso-OMPA, Mipafox

Abstract

Rats treated daily with diisopropylfluorophosphate (DFP) (0.5 mg/kg, sc), an inhibitor of acetylcholinesterase (AChE) activity, exhibited the symptoms of cholinergic hyperactivity between Days 3 and 5 similar to those observed 15 min after a single acute dosage (1.5 mg/kg, sc). A significant (p less than 0.05) decrease in the activities of both AChE and cholinesterase (BuChE) (greater than 80%) occurred in muscles and in brain regions and of aliesterases in liver (greater than 92%) at this time. Further administration of DFP (0.5 mg/kg, for 7-14 days) led to behavioral tolerance, where symptoms of toxicity disappeared such as muscle fasciculations, tremors, and muscle necrosis. The activity of aliesterases in liver and AChE in muscles significantly (p less than 0.01) recovered, while no such recovery was seen in brain AChE. DFP toxicity was potentiated in rats that were pretreated with BuChE inhibitors, such as iso-OMPA (3 mg/kg, sc) or mipafox (0.05 mg/kg, sc), 30 min prior to DFP (0.5 mg/kg, sc). The severity of cholinergic hyperactivity and inhibition of aliesterase in liver, AChE and BuChE activity in brain and muscles was greater when compared to the effects of DFP alone. Both iso-OMPA and mipafox completely abolished the tolerance development to DFP, since no animal survived more than 5 days of combined treatment. The observed adaptation to DFP toxicity appears to be due to recovery of aliesterase, BuChE, and AChE activity as well as decreased nicotinic binding sites at the neuromuscular junction, as previously reported.



        

Title: Brain cholinergic, behavioral, and morphological development in rats exposed in utero to methylparathion
Gupta RC, Rech RH, Lovell KL, Welsch F, Thornburg JE
Ref: Toxicol Appl Pharmacol, 77:405, 1985 : PubMed
Abstract


ESTHER: Gupta_1985_Toxicol.Appl.Pharmacol_77_405
PubMedSearch: Gupta 1985 Toxicol.Appl.Pharmacol 77 405
PubMedID: 3975908
Inhibitor(s) related to this paper: Methylparathion

Abstract

The purpose of this study was to determine the effects of subchronic administration of the organophosphate methylparathion (MPTH) during gestation on behavior and development of brain cholinergic neurons in the offspring. Pregnant rats received daily po doses of MPTH from Day 6 through Day 20 of gestation at doses causing no (1.0 mg/kg) or minimal (1.5 mg/kg) visible signs of maternal toxicity. Acetylcholinesterase (AChE) and choline acetyltransferase (CAT) activities, and [3H]quinuclidinyl benzilate (QNB) binding to muscarinic receptors, were determined in several brain regions at 1, 7, 14, 21, and 28 days postnatal age and in maternal brain at Day 19 of gestation. Prenatal exposure to 1.5 mg MPTH/kg reduced AChE and increased CAT activity in all brain regions at each developmental period and in maternal brain. Similar exposure to 1.0 mg MPTH/kg caused a significant but smaller and less persistent reduction in AChE activity but no change in brain CAT activity of the offspring. Both doses of MPTH decreased the Bmax of 3H-QNB binding in maternal frontal cortex but did not alter the postnatal pattern of 3H-QNB binding. In parallel studies, prenatal exposure to MPTH did not affect a variety of behaviors. However, cage emergence, accommodated locomotor activity, and operant behavior in a mixed paradigm were impaired in rats exposed to 1.0 but not to 1.5 mg/kg MPTH. No morphological changes were observed in hippocampal or cerebellar tissue. Thus, subchronic prenatal exposure to MPTH altered postnatal development of cholinergic neurons and caused subtle alterations in selected behaviors of the offspring.